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Evidence Based Clinical Practice Guidelines on the Diagnosis and


Management of Breast Cancer.
Part II.Locally Advanced Breast Cancer, Locally Recurrent Breast Cancer, and
Metastatic Breast Cancer
Maria Lourdes De Leon Matsuda,M.D.,F.P.C.S.1; Adriano V. Laudico,
M.D.,F.P.C.S.1;Nelson D. Cabaluna, M.D., F.P.C.S1; Victor Ernesto D. Yosuico, M.D.,
F.P.C.P2 Mark R. Kho M.D.,F.P.C.S.1; Orlino C. Bisquera,Jr., M.D.,F.P.C.S1 ; Frances J.
Blanco, M.D1
1 Department of Surgery, College of Medicine and Philippine General Hospital, University of the
Philippines Manila
2 Section of Medical Oncology, College of Medicine and Philippine General Hospital, University
of the Philippines Manila.

STARTER STATEMENT
This information, based on the Philippine College of Surgeons (PCS) Clinical Practice
Guidelines, is intended to assist doctors and patients in the management of breast
cancer. The PCS Clinical Practice Guidelines were developed by a diverse panel of
experts. The guidelines are a statement of the Philippine College of Surgeons regarding
the scientific evidence and its views of currently accepted approaches to treatment.
These guidelines are not intended to replace, but to assist the expertise and clinical
judgment of physicians on the management of individual patients. Each patients
situation must be evaluated individually. It is important to discuss the guidelines and all
information regarding treatment options with the patient.

EXECUTIVE SUMMARY
The clinical area identified by the Philippine College of Surgeons (PCS) for the third
evidence based clinical practice guidelines (EBCPGs) was on the management of breast
cancer. Funding for the research project was provided by the Philippine Council for
Health Research and Development (PCHRD). A Technical Working Group (TWG) was
formed, composed of 6 general surgeons and 1 medical oncologist. The TWG was
tasked to identify the clinical questions and to adhere to the PCS approved method of
developing EBCPGs. The TWG divided the report into two parts: Part I. Early Breast
Cancer, Part II. Locally Advanced Breast Cancer, Locally Recurrent Breast Cancer, and
Metastatic Breast Cancer. The report on Part I. Early Breast Cancer has been published
(Philipp J Surg Spec 2001; 56 (1) : 7-30) .
The TWG began work on part II of the EBCPG on breast cancer in January 2001.
Electronic search of the Medline, Cochrane (Issue 2, 2001), and Herdin (version I, 1997)
databases were done using the search (MeSH) terms locally advanced breast cancer,
local recurrence in breast cancer, and metastatic breast cancer and treatment.

For locally advanced breast cancer, the search was limited to English
publications, reviews, randomized controlled trials (RCTs), and clinical trials. There
were no meta-analyses or systematic overviews found. A manual search was also done
using the reference lists of the relevant articles. For locally recurrent breast cancer, the
search was limited to RCTs, cohort studies,case series reports and review articles in the
English language. There were also no meta-analyses or systematic overviews found.
Reference lists of the relevant articles were likewise manually searched. For metastatic
breast cancer, the search was limited to RCTs and meta analyses in the English
language.Manual searching of the reference list of the meta-analyses and important
RCTs were also done.
The primary outcome of interest for the treatment options was survival (overall
and disease free). Complications of treatment and morbidity rates were also included for
aggressive chest wall resection for local recurrence because it was deemed important to
discourage its practice as standard treatment. Impact on survival was also the main
outcome of interest on the question regarding metastatic work-up in locally advanced
breast cancer. For the clinical questions on detection and diagnosis of locoregional
recurrence, test characteristics of the various procedures were reported as secondary
outcomes of interest. However, and more importantly, studies which showed their
impact on survival were also reported.
The TWG classified the evidence according to three levels and proposed a first
draft of recommendations according to three categories:
LEVELS OF EVIDENCE
I.

Evidence from at least one properly designed randomized controlled trial or


meta-analysis.

II.

Evidence from at least one well designed clinical trial without proper
randomization, from prospective cohort or case control analytic studies
(preferably from one center), from multiple time series studies, or from
dramatic results in uncontrolled experiments.

III.

Evidence from opinions of respected authorities on the basis of clinical


experiences, descriptive studies, or reports of expert committees.

CATEGORIES OF RECOMMENDATIONS
Category A : Recommendations that were approved by consensus ( 75 % of the
multisectoral expert panel )
Category B :
Category C :

Recommendations that were somewhat controversial and did not meet


consensus.
Recommendations that caused real disagreements among members of the
panel.

The following clinical questions were formulated:


A. Locally Advanced Breast Cancer
1. What is the operational definition of the term locally advanced breast cancer ?
2. Is it necessary to perform intensive metastatic work-up for asymptomatic patients
with locally advanced breast cancer? What is the magnitude of the survival benefit, if
any?
3. What are the benefits in terms of disease free survival (DFS) and overall survival of
locoregional treatment /s (surgery, radiotherapy, or surgery plus radiotherapy) in
locally advanced breast cancer?
4. What are the benefits in terms of disease free survival (DFS) and overall survival of
systemic treatments (hormonal and / or chemotherapy) in locally advanced breast
cancer?
B. Locally Recurrent Breast Cancer
1. What are the methods currently used for the early detection of locoregional recurrence
(LRR) and what are their test characteristics?
2. What is the impact on survival of early detection of LRR?
3. What are the methods currently used for the diagnosis of LRR and what are their test
characteristics?
4. What are the benefits in terms of disease free survival (DFS) and overall survival of
locoregional treatments (surgery and/or radiotherapy) in locally recurrent breast
cancer?
5. Will adding systemic treatment (chemotherapy, hormonal therapy, or combination
of both) improve recurrence free and overall survival after potentially curative local
treatment of isolated LRR?
C. Metastatic Breast Cancer
1. Does systemic chemotherapy or hormonal therapy confer a survival benefit for
patients with metastatic breast cancer ? If so, what is the magnitude of the survival
benefit?
2. Which is the better initial treatment modality for metastatic breast cancer: systemic
chemotherapy or hormonal therapy?

3. What are the survival benefits of the different hormonal therapies in metastatic breast
cancer?
4. What are the survival benefits of the different chemotherapy regimens in metastatic
breast cancer?
5. Will the addition of chemotherapy to hormonal therapy or the addition of hormonal
therapy to chemotherapy confer a survival benefit for patients with metastatic breast
cancer?
6. Are there other treatments which have shown survival or palliative benefits in
metastatic breast cancer? If so, what are these modalities and what are their survival
or palliative benefits, if any?
The TWG prepared a first draft of the manuscript which consisted of a summary
of the strongest evidence associated with the clinical questions and suggested
recommendations. The first draft was discussed and modified by a Panel of Experts
convened by the PCS on September 22, 2001 at the PCS building. A second draft was
prepared by the TWG and this was discussed in a Public Forum on December 5, 2001
during the 57th Clinical Congress of the PCS held at the EDSA Shangrila Hotel. The
guidelines were then approved by the PCS Board of Regents on January 5, 2002.

Recommendations
A. Locally Advanced Breast Cancer
1. Breast cancer cases which are included in the definition of the Early Breast Cancer
Trialists Collaborative Group (EBCTCG), namely cases wherein cancer is restricted to the
breast and, in the case of node positive patients, the local lymph nodes can be removed
surgically, should be managed according to the PCS evidence based clinical practice
guidelines on early breast cancer (Philipp J Surg Spec 2001; 56(1):7-36). (Level I, Category
A)
2. The term locally advanced breast cancer shall from now on be used for cases that are not
considered early breast cancer and have no evidence of distant metastasis. This will comprise
T4 tumors or stage IIIB cases. (Level II, Category A)
3. Diagnostic tests for detection of distant metastases in patients with locally advanced breast
cancer should be individualized and symptom-directed; and not done routinely. Physicians
should do exhaustive search for clinical evidence of distant metastases by doing thorough
history and physical examination.(Level II, Category B)
4. There seems to be some evidence that for locally advanced breast cancer, the use of systemic
therapy and radiotherapy may increase survival, but the size and duration of the benefit is
unclear.(Level II, Category A)

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5. In some cases, neoadjuvant systemic therapy may reduce primary tumor size to such an
extent that may permit mastectomy or even breast conserving surgery. (Level II, Category A)
B. Locally Recurrent Breast Cancer
1. Physical examination alone adequately detects locoregional recurrence due to breast
cancer in most cases. ( Level II, Category A )
2. Periodic follow-up aimed at early detection of local recurrences of breast cancer may
be recommended, although the prognostic impact of such a policy is probably limited.
( Level II, Category A )
3. Cytologic or histologic documentation of recurrent disease should be obtained whenever
possible, prior to active treatment. ( Level III, Category A )
4. Core needle biopsy (CNB) is the initial diagnostic procedure in breast cancer patients with a
palpable locoregional recurrence. ( Level III, Category A )
5. Open biopsy, whenever possible, may be done for histologic documentation of recurrent disease
when the initial CNB yields unsatisfactory results.( Level III, Category A )
6. The determination of estrogen receptor ( ER ) status of the local recurrence is encouraged.
However, women with locally recurrent breast cancer with unknown estrogen receptor status
are managed as estrogen receptor positive tumors. ( Level III, Category A )
7. Metastatic work up to evaluate extent of disease is recommended prior to treatment for
recurrent breast cancer. ( Level III, Category A )
8. Salvage mastectomy is the standard treatment for locoregional control of recurrence after
breast conservation treatment. ( Level II, Category A )
9. Radiotherapy is given for locoregional control of locally recurrent breast cancer appearing
after initial treatment with mastectomy. ( Level II, Category A )
10. Surgical resection of local soft tissue recurrence after initial treatment with mastectomy may
be done prior to radiotherapy, for local recurrences measuring 3 centimeters or less, which
could be excised completely and safely, recurring 2 years or more after primary treatment.
(Level II, Category A )
11. Aggressive chest wall resection of locally recurrent breast cancer is not recommended because
it carries a high morbidity rate and there is no proven survival benefit. ( Level II, Category A)
12. For patients with locally recurrent breast cancers which are estrogen receptor positive,
hormonal therapy is the initial systemic treatment given. ( Level I, Category A )

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13. Tamoxifen is the preferred first-line hormonal therapy for patients with locally recurrent
breast cancers which are estrogen receptor positive.(Level I, Category A) Tamoxifen is given
at a dose of 20 mg daily and is given continuously even if there is complete response, until
disease progression. ( Level III, Category A )
14. For elderly postmenopausal women with long disease free interval ( 2 years between
primary treatment and local recurrence ) whose recurrence is confined to skin and soft tissue,
locoregional treatment may not be done and tamoxifen alone may be given.
( Level III, Category A )
15. For patients with locally recurrent breast cancers which are estrogen receptor negative,
chemotherapy may increase survival but the size and duration of the benefit is unclear.
(Level II, Category A )
C. Metastatic Breast Cancer
1. The primary goal of therapy for patients with metastatic breast cancer is palliation. Palliative
care is the active total care of patients whose disease is no longer responsive to curative
treatment. The goal of palliative care is achievement of the best possible quality of life for
patients and their families. Control of pain and of other symptoms, and alleviation of
psychological, social, and spiritual problems are paramount. ( Level III , Category A )
2. The WHO method of cancer pain relief should be immediately started for all patients with
metastatic breast cancer who complain of pain. ( Level III , Category A )
3. In general, for patients with metastatic breast cancer, systemic chemotherapy may be offered
because it has been shown to confer a modest survival benefit of 6-9 months.
( Level II, Category A )
4. The determination of estrogen receptor ( ER ) status of the metastatic lesion is encouraged.
However, patients with metastatic breast cancer with unknown estrogen receptor status are
managed as estrogen receptor positive tumors. ( Level III, Category A )
5. For patients with metastatic breast cancer which are estrogen receptor positive,
hormonal therapy is the initial systemic treatment given. ( Level II, Category A )
6. Tamoxifen is the preferred first-line hormonal therapy for patients with metastatic breast
cancer which are estrogen receptor positive. (Level I, Category A) Tamoxifen is given at a
dose of 20 mg daily and is given continuously, even if there is complete response, until disease
progression.( Level I, Category A )
7. Patients with metastatic breast cancer who responded to tamoxifen initially are offered second
line hormonal therapies at the time of disease progression. ( Level I, Category A )
8. For patients with metastatic breast cancer which are estrogen receptor negative, chemotherapy
may increase survival but the size and duration of the benefit is unclear. (Level II, Category A)

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9. There is no survival benefit among the different polychemotherapy regimens. Continued
therapy until disease progression is better compared to limited therapy. However, drug
toxicity and complications of chemotherapy should be given serious consideration bearing in
mind that palliation of symptoms and not tumor response is the main goal of therapy.
( Level I, Category A )
10. The addition of chemotherapy to hormonal therapy does not confer a survival benefit for
patients with metastatic breast cancer who are already responding to hormonal therapy.
Likewise, the addition of hormonal therapy to chemotherapy does not confer a survival benefit
for patients with metastatic breast cancer who are already responding to chemotherapy.
( Level I, Category A )
11. Radiotherapy may be given to symptomatic patients with bone metastases for relief
of symptoms. ( Level I, Category A )
12. For patients with bone metastases, bisphosphonates may be given because they reduce the
incidence of skeletal complications and decrease pain medication requirements; however, no
survival benefit has been observed. ( Level I, Category A )
Technical Working Group
Principal Investigator:
Maria Lourdes De Leon Matsuda (general surgeon)
Members:
Adriano V. Laudico (general surgeon)
Nelson D. Cabaluna (general surgeon)
Victor Ernesto D. Yosuico (medical oncologist)
Mark Richard Kho (general surgeon)
Orlino C. Bisquera Jr. (general surgeon)
Frances J. Blanco (general surgeon )
Research Assistant:
Ruth D. Nituda
Panel of Experts:
1. Leonardo L. Cua (general surgeon, PCS Board of Regents)
2. Rey Melchor F. Santos (general surgeon, PCS Board of Regents)
3. Ray B. Malilay (general surgeon, PCS Board of Regents, Philippine Society of
General Surgeons)
4. Edilberto Fragante ( Radiation Oncologist, Philippine Radiation Oncology Society)
5. Emelito A. Roxas ( representing Dr. Ernesto C. Tan of the PCS Board of Regents )
6. Wyda D. Beria (physician, Degenerative Diseases Office - Department of Health )

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ACKNOWLEDGEMENT
This project was supported by a research grant to the Philippine College of
Surgeons from the Philippine Council for Health Research and DevelopmentDepartment of Science and Technology.
BACKGROUND
The Philippine College of Surgeons ( PCS ) had identified the development,
dissemination and implementation of evidenced - based clinical practice guidelines
(EBCPG), as an important strategy in improving surgical care, training and research.
The Philippine Council for Health Research and Development ( PCHRD ) of the
Department of Science and Technology ( DOST ) had also identified the development of
EBCPGs as one of the top priorities in the national research agenda, and in 1999 the
DOST PCHRD, PCS and the Department of Surgery of the University of the
Philippines Manila College of Medicine signed a trilateral Memorandum of Agreement
on the development of EBCPGs on certain areas of surgical care in the Philippines.
These areas of surgical care should be those wherein current practice may not be truly
evidence- based, which have a large potential of improving major outcomes and even
decreasing costs; furthermore, the EBCPGs should be implementable nationwide in both
government and private health facilities. The first PCS-EBCPG was on seeking referral
for perioperative cardiac evaluation for noncardiac surgery and when the intraoperative
presence of a cardiologist / internist would be beneficial.1 The second PCS EBCPG was
on some important aspects in the care of critically ill surgical patients. 2
This project is the third PCS EBCPG and aims to produce guidelines on the
diagnosis and management of breast cancer.
Breast cancer had consistently been the most common cancer among Filipino
women. With an age standardized incidence rate ( ASR ) of 47.7 per 100,000 women
(1998), it was second only to lung cancer when both male and female cancers were
considered. ASRs had increased ( 1980-1992 ), and ASRs of female residents in highly
urbanized cities in Metro Manila were already similar to some populations in Europe,
South America and Oceania. One out of 28 Filipinos who live up to 64 years, and one of
19 who live up to 74 years will have breast cancer.3 In 1998, an estimated 9,325 new
cases would have occured in the country.4
In the absence of evidence based clinical practice guidelines, there exists wide
variations regarding important aspects in the diagnosis and management of breast
cancer. These controversies continue to have a serious impact on the quality of care,
as well as on the judicious utilization of resources. Furthermore, owing to the large
number of publications on breast cancer in the medical literature, in lay periodicals, as
well as on the internet, incomplete or even erroneous information may be provided to
physicians and patients leading to wrong perceptions that seriously affect the
management of breast cancer.

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METHODS
The PCS appointed a Technical Working Group (TWG) composed of 6 general surgeons
and 1 medical oncologist. The group was instructed to adhere to the methods used in the
development of the guidelines used on the first two PCS EBCPGs ( Roxas 1999, Laudico
2000 ) . The group was also given a free hand to formulate the specific clinical questions
on areas considered important in the diagnosis and management of breast cancer. The
TWG decided to divide the report into 2 parts: Part I. Early Breast Cancer and Part II.
Locally Advanced Breast Cancer, Locally Recurrent Breast Cancer and Metastatic Breast
Cancer. The report on Part I. Early Breast Cancer has been published (Philipp J Surg
Spec 2001; 56(1):7-30).
The TWG began work on part II of the EBCPG on Breast Cancer in January 2001.
Electronic search of the Medline, Cochrane (Issue 2, 2001), and Herdin (version I, 1997)
databases were done using the search (MeSH) terms locally advanced breast cancer,
local recurrence in breast cancer, and metastatic breast cancer and treatment.
For locally advanced breast cancer, the search was limited to reviews,
randomized controlled trials (RCTs), and clinical trials in the English language. There
were no meta-analyses or systematic overviews found. A manual search was also done
using the reference lists of the relevant articles. There were 299 titles obtained, out of
which 206 were chosen for review of abstracts. Only 43 full text articles were retrieved
and appraised, and 10 articles were chosen for the final paper.
For locally recurrent breast cancer the search was limited to RCTs, cohort
studies,case series reports and review articles in the English language. There were also
no meta-analyses or systematic overviews found. A manual search was also done using
the reference lists of the relevant articles. There were 288 titles obtained from the
Medline and 28 articles in the Cochrane Library, out of which 173 were chosen for
review of abstracts. Seventy one full text articles were retrieved and appraised, 31
articles were chosen as the evidence in the formulation of the recommendations.
For metastatic breast cancer the search was limited to RCTs and meta analyses in
the English language.The search yielded 504 titles from the Cochrane Library and 6,326
titles from Pubmed. There were 12 meta analyses and 470 RCTs. Sixty seven titles were
chosen for review of abstracts, 33 full text articles were retrieved and appraised and 20
articles were chosen for the final paper.
The primary outcome of interest for the treatment options was survival (overall
and disease free). Complications of treatment and morbidity rates were also included for
aggressive chest wall resection for local recurrence because it was deemed important as
to discourage its practice as standard treatment. Impact on survival was also the main
outcome of interest on the question regarding metastatic work-up in locally advanced
breast cancer. For the clinical questions on detection and diagnosis of locoregional
recurrence, test characteristics of the various procedures were reported as secondary
outcomes of interest. However, and more importantly, studies which showed their
impact on survival were also reported.

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The TWG then compiled, summarized and classified the evidence according to 3 levels
and proposed a first draft of recommendations according to 3 categories:
LEVELS OF EVIDENCE
I.

Evidence from at least one properly designed randomized controlled trial or


meta-analysis.

II.

Evidence from at least one well designed clinical trial without proper
randomization, from prospective cohort or case control analytic studies
(preferably from one center), from multiple time series studies, or from
dramatic results in uncontrolled experiments.

III.

Evidence from opinions of respected authorities on the basis of clinical


experiences, descriptive studies, or reports of expert committees.

CATEGORIES OF RECOMMENDATIONS
Category A : Recommendations that were approved by consensus ( 75 % of the
multisectoral expert panel )
Category B :

Recommendations that were somewhat controversial and did not meet


consensus.

Category C :

Recommendations that caused real disagreements among members of the


panel.

The following clinical questions were formulated:


A. Locally Advanced Breast Cancer
1. What is the operational definition of the term locally advanced breast cancer ?
2. Is it necessary to perform intensive metastatic work-up for asymptomatic patients
with locally advanced breast cancer? What is the magnitude of the survival benefit, if
any?
3. What are the benefits in terms of disease free survival (DFS) and overall survival of
locoregional treatment /s (surgery, radiotherapy, or surgery plus radiotherapy) in
locally advanced breast cancer?
4. What are the benefits in terms of disease free survival (DFS) and overall survival of
systemic treatments (hormonal and / or chemotherapy) in locally advanced breast
cancer?

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B. Locally Recurrent Breast Cancer
1. What are the methods currently used for the early detection of locoregional recurrence
(LRR) and what are their test characteristics?
2. What is the impact on survival of early detection of LRR?
3. What are the methods currently used for the diagnosis of LRR and what are their test
characteristics?
4. What are the benefits in terms of disease free survival (DFS) and overall survival of
the following locoregional treatments (surgery and/or radiotherapy) in locally
recurrent breast cancer?
5. Will adding systemic treatment (chemotherapy, hormonal therapy, or combination
of both) improve recurrence- free and overall survival after potentially curative local
treatment of isolated LRR?
C. Metastatic Breast Cancer
1. Does systemic chemotherapy or hormonal therapy confer a survival benefit for
patients with metastatic breast cancer ? If so, what is the magnitude of the survival
benefit?
2. Which is the better initial treatment modality for metastatic breast cancer: systemic
chemotherapy or hormonal therapy?
3. What are the survival benefits of the different hormonal therapies in metastatic breast
cancer?
4. What are the survival benefits of the different chemotherapy regimens in metastatic
breast cancer?
5. Will the addition of chemotherapy to hormonal therapy or the addition of hormonal
therapy to chemotherapy confer a survival benefit for patients with metastatic breast
cancer?
6. Are there other treatments which have shown survival or palliative benefits in
metastatic breast cancer? If so, what are these modalities and what are their survival
or palliative benefits, if any?

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Results

A. Locally Advanced Breast Cancer


1. What is the operational definition of the term locally advanced breast cancer ?
Locally advanced breast cancer (LABC) has been defined by many investigators
as T3-4 primary cancer or N2-3 lymph node metastases. This includes Stages IIB, IIIA
and IIIB of the UICC/AJCC Staging System and overlaps with the definition of early
breast cancer by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) which
includes Stages I IIIA. This definition of early breast cancer has been adopted by the
PCS, and used in Part I of the PCS Clinical Practice Guidelines on Breast Cancer. The
lack of a globally standardized definition of LABC is a major cause of controversy
regarding its treatment. It also supports the EBCTCG definition of early breast cancer
which will include most stage IIIA cases whose relative 5-year survival probability was
56 per cent. In contrast, stage IIIB cases, many of which will be excluded from the
EBCTCG definition of early breast cancer had a lower 5-year relative survival
probability of 49 per cent. Table 1 shows American registry data on relative 5-year
survival by stage.5 These data show the broad range of survival rates among patients
who are included in the many definitions of locally advanced breast cancer.
Breast cancer cases which are neither covered by the EBCTCG definition of
early breast cancer, nor satisfy the criteria for metastatic breast cancer, will now be
labeled locally advanced breast cancer. Essentially, this will comprise T4 tumors or
Stage III B cases .
Recommendations:
1. Breast cancer cases which are included in the definition of the Early Breast Cancer Trialists
Collaborative Group (EBCTCG), namely cases wherein cancer is restricted to the breast and,
in the case of node positive patients, the local lymph nodes can be removed surgically, should
be managed according to the PCS evidence based clinical practice guidelines on early breast
cancer (Philipp J Surg Spec 2001; 56(1):7-36). ( Level I, Category A )
2. The term locally advanced breast cancer shall from now on be used for cases that are not
considered early breast cancer and have no evidence of distant metastasis. This will comprise
T4 tumors or stage IIIB cases.( Level II, Category A )
2. Is it necessary to perform intensive metastatic work-up for asymptomatic patients
with locally advanced breast cancer? What is the magnitude of the survival benefit,
if any?
A retrospective study by Ciatto6 in 1985 reported on a consecutive series of 3,627
histologically confirmed breast cancer patients who underwent preoperative staging
examinations in 11 Italian centers from 1973-1985. Of the 3,627 cases, there were 265
Stage IIIA and 417 Stage III B patients who underwent tests consisting of chest x-ray,
bone x-ray, bone scan , and liver echography. The detection rate of asymptomatic distant

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metastases on these examinations are shown in Table 2. Detection rates were around 1 to
2 per cent.
It was also shown that to detect one case of asymptomatic distant metastasis, a
large number of examinations had to be done. Table 3 shows that for Stage IIIB cases, it
will take 83 chest x-rays and 75 bone scans to detect one metastasis.
After searching the literature, no study was found which addressed the issue of,
or which provided evidence that early detection of distant metastases resulted in an
improvement in survival. However, since detection of distant metastases in a patient
with locally advanced breast cancer could change management, and since most reviews
7, 8 would still conclude that majority of breast cancer patients with distant metastases
have some clinical sign or symptom; physicians are advised to do exhaustive search for
clinical evidence of distant metastases by doing thorough history and physical
examination. Requesting for metastatic work-up for patients with locally advanced
breast cancers should be individualized and done on a case to case basis.
Recommendation:
3. Diagnostic tests for detection of distant metastases in patients with locally advanced breast
cancer should be individualized and symptom-directed; and not done routinely. Physicians
should do exhaustive search for clinical evidence of distant metastases by doing thorough
history and physical examination. (Level II, Category B )
3. What are the benefits in terms of disease free survival (DFS) and overall survival of
locoregional treatment /s (surgery, radiotherapy, or surgery plus radiotherapy) in
locally advanced breast cancer?
The management of LABC has evolved from no treatment to locoregional
therapies to the multimodal therapy that is favored by most breast centers today. There
are only few clinical trials that compare purely locoregional with a combination of
locoregional and systemic therapies and they have small sample sizes. There are also a
number of reported case series on multimodal therapy which are uncontrolled. A review
of studies before the advent of systemic therapies may allow some indirect comparisons.
It would seem worthwhile to look at data from untreated cases of locally
advanced breast cancer to realize the impact of present treatment. Bloom et al9
examined the natural history of 250 untreated breast cancer patients who were admitted
to Middlesex Hospital from 1805-1933. Two hundred forty four (97.6%) of these patients
were either Stage III (58) or Stage IV (186) based on the Manchester classification. Stage
III was defined as tumor invading the skin or underlying muscle with or without
movable axillary nodes and Stage IV as tumor fixed to chest wall, matted axillary nodes,
deposits in supraclavicular nodes or distant metastases. All patients died in the hospital
and were subjected to necropsy. Survival, measured from time of onset of symptoms
was 18 per cent at 5 years, 4 per cent at 10 years and 0.8 per cent at 15 years with a
median survival of 2.7 years.9

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Hortobagyi and Buzdar10 summarized the data from more than 30 studies of
LABC that were treated by locoregional therapy alone. No significant difference was
noted between the mean survival at 5 and 10 years for patients treated by surgery,
radiotherapy or surgery plus radiotherapy. Five year and 10 year survival rates for all
treatments were approximately 32 per cent and 20 per cent , respectively. There were
however, wide ranges in survival statistics which may be due to variations in number of
patients and staging accuracy. Survival ranged from 3 to 61 per cent for surgery alone,
1 to 66 per cent for radiotherapy alone and 12 to 53 per cent for combined surgery and
radiotherapy. Median disease-free survival was 8-12 months and median survival
approximately 24 months or 2 years.
Indirect comparison with natural history data suggests that locoregional
treatment does not produce improvement in survival. It must be emphasized however,
that there are numerous limitations to using historical controls, particularly those that
are based on retrospective data. Furthermore, Blooms survival data was measured
from onset of symptoms, and not from date of diagnosis.
4. What are the benefits in terms of disease free survival (DFS) and overall survival of
systemic treatments (hormonal and / or chemotherapy) in locally advanced breast
cancer?
The results of three randomized controlled trials on combined locoregional and
systemic therapies are summarized in Table 4. Olson et al for the Eastern Cooperative
Oncology Group (ECOG)11 reported on the role of radiotherapy in the management of
operable locally advanced breast cancer. After undergoing mastectomy, 383 patients
were treated with 6 courses of chemohormonal therapy. Fifty three per cent were Stage
IIIA and 40 per cent Stage IIIB. Three hundred twelve patients who remained without
recurrence after mastectomy and chemohormonal therapy were then randomized to
receive radiotherapy of 46 gray over 4 weeks to the chest wall and regional lymph
node areas or to observation alone. One hundred sixty four patients were randomized
to radiotherapy and 148 to observation. Patients in the observation arm who developed
locoregional recurrence with no distant metastases were offered radiotherapy but were
analyzed according to their original randomization. After 9.1 years of median follow up,
median survival was 8.3 years for radiotherapy and 8.1 years for observation. There
were virtually identical relapse and survival rates in the two treatment arms. There
were more locoregional recurrences as sites of first relapse in the observation group
while there were more distant metastases in the radiotherapy arm. Twenty nine patients
(20%) had locoregional recurrence and 45 (30%)had distant metastases as site of first
relapse in the observation arm, while 14 patients (9%) had locoregional recurrence and
72 (44%) had distant metastases in the radiotherapy arm.
Koning and Hart12 reported a randomized trial in the Netherlands conducted
from 1977 to 1980. They reported on a 14-year follow up of 118 patients who were
randomized between radiotherapy alone; radiotherapy(RT), 12 courses of CMF and
tamoxifen(RT/CMFT); and adriamycin, vincristine (AV) alternated with CMF, then
radiotherapy, followed by four cycles of AV/CMF and tamoxifen during the entire
treatment period. Aside from the usual signs of locally advanced breast cancer, patients

15
must have had a positive axillary apex biopsy which was considered a sign of advanced
locoregional disease. The survival curves for the three treatment arms were almost
identical for the first 6 years. Thereafter, the survival curves grew apart, resulting in
differences in 10-year survival rates, up to 15 per cent between arms III and I, but not
reaching statistical significance (p=0.38, 95% confidence interval = -3 to 33%). Disease
free survival data are shown in Table 5. This study was discontinued so as to take part
in the EORTC trial. Owing to the small number of patients, the relative value of the
various treatments cannot be established.
Bartelink13 reported an 8-year follow up of a European Organization for Research
and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group trial which
randomly allocated 410 patients from 1979-1985 to receive radiotherapy (RT) alone, RT
with chemotherapy(CT), RT with hormonotherapy (HT), or RT with CT and HT. Of the
374 evaluable patients, 29.7 per cent were Stage IIIA, 43 per cent Stage IIIB, 24.3 per cent
not Stage III, and 3 per cent unknown stage. Results of treatment were not reported
according to specific stage. Analysis of results performed 8 years after trial closure
showed a significantly improved survival in patients treated with HT(p=0.04) but not
with CT(p=0.21). The median duration of survival in patients who received adjuvant
HT was 4.3 years, as opposed to 3.3 years in those who did not receive HT. For CT, the
medians were 3.8 years and 3.6 years, respectively. The combined treatment with HT
and CT provided the greatest therapeutic effect(p=0.02), with median survival of about 5
years.
In this EORTC trial, both CT (p=0.0002) and HT (p=0.0007) significantly delayed
the time to locoregional recurrence with the combined treatment group experiencing the
greatest therapeutic effect (p=0.0001). The locoregional recurrence rate was reduced
from 59 per cent to 48 per cent at 6 years in patients who received CT, and from 61 per
cent to 47 per cent in patients who received HT.
There were also a number of case series reports on combined locoregional and
systemic therapy for LABC. Hortobagyi14 reported on the M.D. Anderson experience
with 174 patients who received 3 cycles of cyclophosphamide, doxorubicin and 5fluorouracil followed by local treatment in the form of mastectomy with axillary
dissection, or radiotherapy or both, then continuation of the chemotherapy. There were
48 patients with Stage IIIA and 126 patients with Stage IIIB. The 5-year disease free
survival rates were 84 per cent for Stage IIIA and 33 per cent for Stage IIIB. The 5-year
overall survival rates were 84 per cent for Stage IIIA and 44 per cent for Stage IIIB.
These figures highlight the big difference between these two Stage III subgroups. In this
series, Stage IIIB patients with good responses to induction chemotherapy had
statistically better prognosis.
Pierce15 et al reported on 107 patients who received chemohormonotherapy to
maximal response followed by local treatment and maintenance therapy. Patients with
a clinical partial response underwent mastectomy and radiotherapy while patients with
a clinical complete response were biopsied. Those with residual disease received
mastectomy/RT while those with pathologic complete response received RT only.
There were 48 Stage IIIA, 46 Stage IIIB-inflammatory ( IBC ), 13 Stage IIIB-non

16
inflammatory ( non IBC ) patients. The 5-year actuarial locoregional failure rate as
first site of failure was 3 per cent for IIIA, 21 per cent for IIIB IBC and 33 per cent for IIIB
non-IBC. The 5-year actuarial locoregional failure rate at first site of failure was 23 per
cent for radiation only versus 5 per cent for mastectomy and post operative
radiotherapy. Five-year survival data are shown in Table 6.
Jacquillat et al16 reported on the results of neoadjuvant chemotherapy and
radiation therapy in a breast conserving treatment of 250 patients. This series included
36 Stage IIIA and 58 Stage IIIB patients. At 5 years, the rate of breast preservation for the
entire group was 94 per cent. The 5-year disease free survival rates were 46 per cent for
Stage IIIA and 52 per cent for Stage IIIB.
Analysis of the data of Olson will show that the survival rates of his patients
were comparable to survival of patients reported by the EBCTCG17 (Table 7), which
leads us to surmise that this population of operable locally advanced breast cancer
may be included in the EBCTCGs definition of early breast cancer. The survival rates in
the two other randomized trials more closely approximated the data reported by the
American College of Surgeons. The patients in these two other trials were a more
heterogeneous mix of operable and inoperable locally advanced breast cancer. We
believe that Stage IIIA has a different prognosis compared to Stage IIIB and it would
seem that within the Stage IIIB group, treatment of operable and inoperable tumors
would also have differing outcomes.
There is evidence that combined locoregional and systemic therapies improved
survival in these heterogeneous groups of locally advanced breast cancer. However,
the benefit to the inoperable cases is unclear because the participation of many
patients with operable breast cancers improved the entire survival picture. Several
clinical trials had also demonstrated good response rates of locally advanced breast
cancer to systemic therapies but whether these responses translated to an improvement
in survival is more difficult to establish.
Recommendations:
4. There seems to be some evidence that for locally advanced breast cancer, the use of systemic
therapy and radiotherapy may increase survival, but the size and duration of the benefit is
unclear. ( Level II, Category A )
5. In some cases, neoadjuvant systemic therapy may reduce primary tumor size to such an
extent that may permit mastectomy or even breast conserving surgery.
( Level II, Category A )
Recommendations for Research
1. There are important unresolved issues in the treatment of inoperable
locally advanced breast cancer. This subset still comprises a big number of
breast cancer cases in developing countries and underscores the urgent need
for clinical trials.

17

2. A comprehensive review of data on locally advanced breast cancer may


allow subset analysis and elucidate differences among patients in this group.
B. Locally Recurrent Breast Cancer
The majority of women with primary breast cancer have apparently operable
disease, and are treated with surgery, and in many cases, with radiotherapy and / or
some form of systemic therapy (such as chemotherapy or tamoxifen). However,
depending on the stage of the disease, and the treatment given, between 10 per cent and
35 per cent of women experience an isolated locoregional recurrence (LRR).18-20 About 80
per cent of these recurrences occur during the first two years after primary treatment.21
Regardless of whether the primary treatment is mastectomy or breast
conservation therapy, locoregional recurrence in breast cancer comprises any
reappearance of the disease in the area of the primary (local) treatment and / or the
regional lymph nodes (axillary, clavicular and parasternal, or internal mammary). It
may be preceded or accompanied by distant metastases. As previously mentioned,
isolated LRR (ie. no overt evidence of distant metastases) accounts for 10-35 per cent of
first breast cancer relapses.
1. What are the methods currently used for the early detection of LRR and what are
their test characteristics?
Early detection and diagnosis of LRR of breast cancer is possible with a variety of
diagnostic methods. A combination of palpation, sonography, and biopsy, eg. aspiration
cytology; and mammography for patients who underwent breast conservation
treatment, is probably as accurate and certainly simpler, faster, and cheaper compared to
other more complicated and costly tests like computerized sonogarphy (CT) and
magnetic resonance imaging (MRI).22
Most LRR are detected by physical examination. Palpation is highly sensitive (70
- 96% sensitivity ) for detecting superficial recurrences in the surgical scar or chest wall.
Retrospective studies showed that as the site of LRR deepened, the sensitivity of
palpation decreased progressively according to site, from supraclavicular to axillary
(especially in the apex) to internal mammary nodes, the latter being palpable only when
they were very large and grew anteriorly through the intercostal spaces.22 The diagnostic
limits of palpation have justified the attempt to improve its accuracy by supplementing
it with other tests.
Sonography is currently used as an adjunct to palpation for the detection of local
recurrences. Retrospective studies showed that the sensitivity of sonography was not
higher when compared to palpation; its accuracy was poor as it often failed to
differentiate between local recurrences and fibrous surgical scarring. However,
sonography was very sensitive for detecting lymph nodes (even of small size) and was
particularly useful to confirm the presence of nodes in the supraclavicular area and the
axilla.23 Unfortunately, differentiating between reactive and metastatic nodes was

18
difficult. Metastatic nodes tended to be more intensely hypoechoic, rounded, and the
hyperechoic hilum was absent.22
Retrospective studies showed that other imaging techniques such as CT and MRI
might detect local recurrences but had no power to distinguish between benign and
malignant masses. 22 Such techniques may be helpful in the internal mammary region
where both palpation and sonography may fail to detect small recurrences, but their use
is generally aimed at staging the extent of disease in the presence of otherwise evident
local recurrences. The routine use of CT scan and MRI in otherwise negative subjects is
not recommended.
Recommendation:
1. Physical examination alone adequately detects locoregional recurrence due to breast cancer in
most cases.( Level II, Category A )
2. What is the impact on survival of early detection of LRR?
Retrospective studies had estimated that periodic observation may detect
asymptomatic local recurrences about 3 months before onset of symptoms.24-25 After
correcting for lead and length time, this presymptomatic detection had a moderate to
null effect on survival from primary treatment. Table 8 shows the results of two
retrospective studies on the prognostic impact of early detection of local recurrences
from breast cancer. The 1985 study shows that the median survival was basically the
same for those women with local recurrences detected earlier even in the
asymptomatic stage (45 months) and those whose recurrences were detected already in
the symptomatic stage (46 months). The limited improvement in median survival among
those whose recurrences were detected earlier in the asymptomatic stage, as reported
in the 1984 study could be possibly explained by length based sampling; that is by
selective concentration of slow growing lesions (long presymptomatic phase) among
asymptomatic recurrences, and of fast growing (short presymptomatic phase) among
symptomatic recurrences.
Because there was no controlled study available to confirm whether such a
diagnostic anticipation has any impact on prognosis, Ciatto in 1995 concluded that
Periodic control aimed at the early detection of these local recurrences might be
recommended, although the prognostic impact (if any) of such a policy is probably
limited, and extremely large controlled studies would be necessary to demonstrate
impact at a significant level.22
Recommendation:
2. Periodic follow up aimed at early detection of local recurrences of breast cancer may be
recommended, although the prognostic impact of such a policy is probably limited.
(Level II, Category A )

19
3. What are the methods currently used for the diagnosis of LRR and what are their
test characteristics?
Cytologic or histologic documentation of recurrent disease should be obtained
whenever possible. Retrospective studies showed that fine needle aspiration cytology
(FNAC) had high accuracy in the diagnosis of local recurrences.22 Table 9 shows the test
characteristics of FNAC in the diagnosis of suspected LRR.
No studies evaluating core needle biopsy (CNB) in diagnosing locally recurrent
breast cancer were found. However, it may be inferred that the high sensitivity and
specificity reported with FNAC can also be obtained, if not surpassed, using larger
CNB. Moreover, CNB will yield more tissue resulting in a lower inadequacy rate.
Therefore, CNB is the initial diagnostic procedure recommended in patients with a
palpable LRR because more tissue will be made available not only for tissue diagnosis,
but also for estrogen receptor status determination.
Open biopsy may be done if CNB yields unsatisfactory results.
Recommendations:
3. Cytologic or histologic documentation of recurrent disease should be obtained whenever
possible, prior to active treatment. ( Level III, Category A )
4. Core needle biopsy ( CNB ) is the initial diagnostic procedure in breast cancer patients with a
palpable locoregional recurrence. ( Level III, Category A )
5. Open biopsy, whenever possible, may be done for histologic documentation of recurrent disease
when the initial CNB done yields unsatisfactory results. ( Level III, Category A )
Recurrent breast cancer is often responsive to therapy, although treatment is
rarely curative at this stage of disease. However, patients with localized breast or chest
wall recurrences may be long term survivors with appropriate therapy. Prior to
treatment for recurrent cancer, restaging to evaluate extent of disease is indicated. As
previously mentioned, cytologic or histologic documentation of recurrent disease should
be obtained whenever possible. The estrogen receptor status (at the time of recurrence,
or during previous primary treatment) should be considered when selecting therapy. ER
status may change at the time of recurrence. In a single small study, 36 per cent of
previously hormone receptor positive tumors were found to be receptor negative in
biopsy specimens of recurrent lesions.26 Patients in this study had no interval treatment.
If ER status is unknown, then the site(s) of recurrence, disease free interval, response to
previous treatment, and menopausal status are useful in selecting between hormone
therapy or chemotherapy as initial systemic treatment.27

20
Recommendations:
6. The determination of estrogen receptor ( ER ) status of the local recurrence is encouraged.
However, women with locally recurrent breast cancer with unknown estrogen receptor status
are managed as estrogen receptor positive tumors. ( Level III, Category A )
7. Metastatic work up to evaluate extent of disease is recommended prior to treatment for
recurrent breast cancer. ( Level III, Category A )
4. What are the benefits in terms of disease free survival ( DFS ) and overall survival
of locoregional treatments (surgery and /or radiotherapy) in locally recurrent breast
cancer ?
Salvage mastectomy is recognized as the standard treatment for breast relapses
after primary treatment with breast conservation. Several retrospective studies showed
that at 5 years, the DFS ranged from 51 to 63 per cent, with an overall survival rate of 48
to 84 per cent. At 10 years, the DFS was 50 to 57 per cent.28-31 It is notable that many of
these women received systemic therapy (hormonal or chemotherapy).
A second breast conserving surgery had been proposed as an alternative to
salvage mastectomy for small recurrent tumors. If the breast had been irradiated after
the initial surgery, additional irradiation is not possible. Two retrospective studies
showed a DFS of 62 to 69 per cent, similar to salvage mastectomy. 30,32 However, this
should be interpreted with caution because of the small patient numbers involved, the
retrospective nature of the studies, and the fact that these were done in highly selected
patients with small recurrences.
Multivariate analysis of the study by Kurtz et al showed that positive or
unknown margins and a short disease free interval (DFI) were predictive of additional
local relapse. For patients who had a relapse in the breast more than 5 years after initial
breast sparing treatment, the subsequent 5- year local control rate was 92 per cent, but
only 49 per cent for patients with shorter DFI . The local control rate after 5 years was 73
per cent in patients with clear margins at the time of resection of the recurrence, but
only 36 per cent for those with positive or unknown margins.32 In short, as Kennedy
pointed out in 1992, Negative margins are essential if additional breast- sparing
surgery is to be considered after initial relapse, and this approach should be considered
only as an alternative to mastectomy in the context of carefully designed and monitored
clinical trials.33
Recommendation:
8. Salvage mastectomy is the standard treatment for locoregional control of recurrence after
breast conservation treatment. ( Level II, Category A )
In contrast to recurrence in the breast, local chest wall recurrence following
mastectomy is usually the harbinger of widespread disease, but in a subset of patients it

21
may be the only site of recurrence. For patients in this subset, surgery and/ or radiation
therapy may be curative.
Halverson et al found that the 5-year locoregional control rate was highest in
patients with isolated chest wall rather than isolated regional nodal or combined chest
wall and nodal recurrences. In addition, the ability to secure and maintain local control
was related directly to the extent of local disease. Tumors that were larger than 3 cm and
could not be excised completely were controlled only 53 per cent of the time, compared
with 85 per cent and 75 per cent for smaller or excisable soft tissue lesions,
respectively.34 Schwaibold et al identified a subgroup of good prognosis patients
with a DFI greater than 2 years, completely excised soft tissue recurrence, and good
locoregional control after radiation therapy, who had a 5-year over all survival rate of 61
per cent.35
In summary, patients with local soft tissue recurrences of less than 3 cm, axillary
and internal mammary node recurrence (as opposed to para-clavicular), and greater
than a 2-year DFI prior to recurrence have the best chance for prolonged survival. The 5year DFS rate in one series of such patients was 25 per cent, with a 10-year DFS rate of 15
per cent; while locoregional control rate was 57 per cent at 10 years.36
Most chest wall tumors can be theoretically resected aggressively, knowing that
stabilization of the chest wall and resurfacing of the defect is possible with current
reconstructive techniques using musculocutaneous flaps, with or without prosthetic
materials. However, aggressive chest wall resection is not commonly done because of
the realization that systemic failure from metastases is the principal limitation in
improving survival. Retrospective studies showed that distant metastases eventually
developed in about 80 per cent of patients after treatment of locoregional recurrence of
breast cancer.37 Moreover there was a repeat local failure rate of 40-50 per cent after
surgical treatment for locally recurrent breast cancer.38 In addition, aggressive chest wall
resections carried high morbidity rates.
One case series done at the M.D. Anderson Cancer Center involved 93 chest wall
resections in 85 patients with a variety of chest wall tumors (excluding T3 lung
carcinomas). There were 47 women and 38 men. The mean and median ages were 46
and 47 years, respectively (range 11 to 81 years). The operative mortality rate was 3.2 per
cent, with major complications in 12.9 per cent. 38 Table 10 shows the complications in
this case series.Two of the four major pulmonary complications resulted in mortality;
one from pneumonia with adult respiratory distress syndrome, and another from
pneumonia with multiple organ failure. One nonpulmonary major complication also led
to death due to ventricular arrhythmias. Preoperative chemotherapy was given to 43
patients (43.8 per cent) and preoperative irradiation was used in 7 patients (8.0 per
cent).38
Nineteen per cent (16/85) of the patients in the M.D. Anderson series underwent
chest wall resection for breast cancer. Of these, 94 per cent (15/16) had locoregional
recurrence. Eleven patients had chest wall recurrence, three had internal mammary node
metastases, and one had an isolated sternal recurrence. Most of the patients had received

22
irradiation either after a primary mastectomy or breast-conserving surgery; or for a
prior local recurrence. The only disease free survivor was a woman still alive 40 months
after resection of a sternal metastasis. All patients surviving beyond 3 years and all but
one of the 8 patients still alive had a disease-free survival of greater than 2 years
between primary treatment and recurrence. Thirty eight per cent (6/16) suffered
additional local recurrences, including the two patients who received radiation before
and after chest wall resection. The repeat local failures occurred 3 to 30 months after the
resection.38
From the data presented, it seems that surgical resection should only be
considered for patients with isolated soft tissue recurrence measuring 3 centimeters or
less, and/or which could be excised completely and safely, recurring 2 years or more
after primary treatment. Postoperative radiotherapy is also given after the surgical
resection if it has not been given previously.
Recommendations:
9. Radiotherapy is given for locoregional control of locally recurrent breast cancer appearing
after initial treatment with mastectomy. (Level II, Category A )
10. Surgical resection of local soft tissue recurrence after initial treatment with mastectomy
may be done prior to radiotherapy, for recurrences measuring 3 centimeters or less, which
could be excised completely and safely, recurring 2 years or more after primary treatment.
(Level II, Category A )
11. Aggressive chest wall resection of locally recurrent breast cancer is not recommended
because it carries a high morbidity rate and there is no proven survival benefit.
( Level II, Category A )
Isolated LRR may be resectable without (this is categorized as RO), or with (RI)
microscopic disease remaining in situ.39 In these cases, the biological significance of LRR
is still not clear. There is an ongoing debate as to whether LRR is generally an indication
of poor prognosis 40-41 or whether resectable LRR is strictly locally confined reappearance
of the disease.42 If the latter is true, complete removal of the LRR should, like a complete
resection of the primary breast cancer, make definitive cure a possibility. However,
when women with resected primary breast cancer who have had LRR are compared
with similar women who have not had LRR, an increased rate of further progress of the
disease is found in the former. The 10-year survival for women with LRR is less than 50
per cent. 39 After potentially curative resection of the primary cancer, adjuvant systemic
treatment has been shown to prolong recurrence-free and overall survival. 17,43
Consequently, it might seem advisable to also use systemic adjuvant therapy after
potentially curative local treatment of LRR.

23
5. Will additional systemic treatment (chemotherapy, hormonal
therapy, or
combination of both) improve recurrence free and overall survival in breast
cancer patients, after potentially curative local treatment of isolated LRR ?
Currently, there is paucity of evidence to recommend routine use of systemic
therapy in patients with locoregional relapse of breast cancer. To date, there is only one
randomized trial published on this topic and this 1994 study of the Swiss Group for
Clinical Cancer Research investigated the role of tamoxifen (TAM) after complete
excision and radiotherapy for isolated LRR in patients with breast cancer.44 One
hundred sixty seven good-risk patients with an estrogen receptor positive (ER+)
recurrence or, in case of unknown receptor status, a DFI greater than 12 months and
three recurrent tumor nodules each 3 cm in diameter, were randomized to observation
subsequent to local treatment or to receive TAM until disease progression. Seventy nine
per cent of the patients were postmenopausal.
The median observation period for the entire study population was 6.3 years.
The median DFS duration was 26 months for observation and 82 months for TAM
patients (p=0.007). This was mainly due to the reduction of further local recurrences,
whereas the occurrence of early distant metastases was delayed. Multivariate analysis
identified DFI and treatment with tamoxifen as significant prognostic factors for DFS.
Systemic therapy with TAM after isolated LRR of breast cancer significantly increased 5year DFS rates from 36 to 59 per cent compared with observation alone. It also
prolonged median DFS by more than 4.5 years in patients with ER positive tumors and
unknown ER status, with DFI greater than 12 months and minimal tumor burden.
However, the 5 year overall survival rate of 76% for those given TAM was not
significantly different from the 74% rate who were treated with observation alone
(p=0.77).Hence the authors concluded that TAM currently has no significant impact on
overall survival, but the median survival duration of the study population has not yet
been reached.44
Recommendations:
12.

For patients with locally recurrent breast cancers which are estrogen receptor positive,
hormonal therapy is the initial systemic treatment given. ( Level I, Category A )

13.

Tamoxifen is the preferred first-line hormonal therapy for patients with locally recurrent
breast cancers which are estrogen receptor positive.(Level I, Category A) Tamoxifen is
given at a dose of 20 mg daily and is given continuously even if there is complete response,
until disease progression. ( Level III, Category A )

14.

For elderly postmenopausal women with long disease- free interval ( 2 years between
primary treatment and local recurrence ) whose recurrence is confined to skin and soft
tissue, locoregional treatment may not be done and tamoxifen alone may be given.
( Level III, Category A )

The randomized study done by the Swiss Group 44 failed to accrue large enough
number of patients to evaluate cytotoxic chemotherapy for estrogen receptor negative,

24
high risk patients with chest wall relapses. To date, there are no published
randomized studies comparing cytotoxic chemotherapy to no treatment following or
simultaneously with local treatment for LRR. What the literature contains are some
retrospective studies which had prognostic factor analysis at first relapse, to identify
subsets of patients who could be considered for systemic cytotoxic chemotherapy at the
time of local relapse.
A brief disease-free interval (DFI) emerged as a consistent prognostic factor
which predicted patients who were at high risk for distant metastases, and who would
therefore possibly benefit from systemic treatment at time of local relapse. The
definition of brief DFI varied with a range of 1 year 40 to 4 years 45. However, majority
of the studies used 2 years as the cut-off to define brief DFI or early relapse 35,42,45,46 .
Data from these studies showed that patients who experienced LRR within the first few
years following original diagnosis had a relatively poor prognosis, with 50 per cent
developing distant metastases compared to only 17 per cent in one series47 among those
who developed the LRR later in the course of the disease. The relatively high distant
metastasis rate of 50 per cent in patients who experienced early LRR may justify
consideration of some form of systemic therapy at the time of local relapse .
Other factors to consider are extent of LRR, hormone receptor status,
menopausal status, histologic grade, and prior systemic therapy. In a retrospective study
of 433 patients with first relapse ( both local and systemic relapse were considered),
Vogel et al found that the median survival time from first relapse (MSFR) ranged from
15 months for poor risk patients with negative ER, DFI of less than 2 years, and visceral
dominant sites, to more than 90 months for good risk patients with positive ER, DFI of
more than 2 years , and soft tissue dominant sites. Although menopausal status alone
was not a significant prognostic variable in regression analysis, 66 per cent of
premenopausal patients had a constellation of poor prognostic variables.45
Based on the data presented, various investigators had concluded that systemic
polychemotherapy should be considered on a case to case basis for patients in this
situation, particularly in the context of a clinical trial.
On the other extreme, Schaibold et al 35 and Kurtz et al48 identified a subgroup of
patients with a DFI greater than 2 years, completely excised recurrence, and good
locoregional control after RT who had a 5-year overall survival rate of 61 per cent, who
would presumably do well without systemic chemotherapy.
Recommendation:
15. For patients with locally recurrent breast cancer which are estrogen receptor negative,
chemotherapy may increase survival but the size and duration of the benefit is unclear.
(Level II, Category A )

25
C. Metastatic Breast Cancer
Metastatic breast cancer is defined as breast cancer occurring anywhere in the
body outside the breast and regional lymph nodes. Common sites of distant spread of
breast cancer are the bones, skin and soft tissues, lungs / pleura, liver and brain. Disease
in the supraclavicular lymph nodes is also considered distant metastases and as such
is also included in Stage IV or metastatic disease.5 In general, when cancer has spread to
distant sites, cure is no longer possible. However,palliation of symptoms can be
achieved in most patients and in some cases the length of survival can be increased.
Before attempting to answer the specific clinical questions formulated in the
treatment of metastatic breast cancer, the TWG first outlined the primary goal of therapy
to serve as a guiding principle and to set the spirit in intervention in the setting of
metastatic breast cancer. This primary goal of PALLIATION, particularly cancer pain
relief, is embodied in the first two recommendations.
Recommendations:
1. The primary goal of therapy for patients with metastatic breast cancer is palliation. Palliative
care is the active total care of patients whose disease is no longer responsive to curative
treatment. The goal of palliative care is achievement of the best possible quality of life for
patients and their families. Control of pain and of other symptoms, and alleviation of
psychological, social, and spiritual problems are paramount. ( Level III , Category A )
2. The WHO method of cancer pain relief should be immediately started for all patients with
metastatic breast cancer who complain of pain. ( Level III , Category A )
1. Does systemic chemotherapy or hormonal therapy confer a survival benefit for
patients with metastatic breast cancer ? If so, what is the magnitude of the survival
benefit?
No studies were found that compared prognosis between patients who were not
given treatment versus those given either chemotherapy or hormonal therapy for
metastatic breast cancer. All the systematic reviews were in agreement that such studies
would have been unethical due to the significant number of tumor responses with
treatment. Data from retrospective studies, a population cohort study from Denmark 49
and several studies based on hospital registries 50,51 indicated that the use of nonanthracycline containing chemotherapy compared with no chemotherapy might add a
survival gain of six to nine months. Hern et al52 analyzed the results from 50 trials
involving 6056 patients to test the hypothesis that if chemotherapy improved survival in
advanced breast cancer, there should be a tendency for the treatment arm demonstrating
higher response rate to also demonstrate a longer survival. A statistically significant
relationship was demonstrated between the relative response rate and median survival
(p < 0.001). It was claimed that effective chemotherapy might prolong the median
survival time by around six months.

26
Recommendation:
3. In general, for patients with metastatic breast cancer, systemic chemotherapy may be offered
because it has been shown to confer a modest survival benefit of 6-9 months. ( Level II,
Category A )
2. Which is better: systemic chemotherapy or hormonal therapy as initial treatment
modality for metastatic breast cancer?
There was no convincing evidence to prove the superiority of chemotherapy
over hormonal therapy or vice versa as initial treatment for metastatic breast cancer.
Based on a two-study analysis, the systematic review of Stockler et al for the National
Health and Medical Research Council ( NHMRC ) Clinical Trials Centre and the
Cochrane Collaboration Collaborative Review Group in Breast Cancer in Australia53
found no significant difference in median survival (18 months each) using either of these
modalities (p=0.73, 95% CI=0.02-60.3), as shown in Table 11 and Figure 1.
Since there was level II evidence which showed that treatment of systemic
recurrence of breast cancer did prolong survival and enhanced quality of life but was
not curative, treatments associated with minimal toxicity are preferred. As such,
hormonal therapy is generally preferred to cytotoxic chemotherapy. Johnston and
Stebbing54 summarized clinical factors that may be used to predict response to hormonal
therapy in metastatic breast cancer based on the Piedmont Oncology Association
Trials55and 4 reviews56-59. These are shown in Table 12.
Recommendations:
4. The determination of estrogen receptor status of the metastatic lesion is encouraged.
However, patients with metastatic breast cancer with unknown estrogen receptor status are
managed as estrogen receptor positive tumors. ( Level III, Category A )
5. For patients with metastatic breast cancer which are estrogen receptor positive, hormonal
therapy is the initial systemic treatment given. ( Level II, Category A )
3. What are the survival benefits of the different hormonal therapies in metastatic
breast cancer?
For patients in whom hormonal therapy is deemed appropriate, tamoxifen is the
preferred first-line hormonal therapy for women who have not received it previously.
The systemic reviews of RCTs from NHMRC Clinical Trials Centre and the Cochrane
systematic review done in Australia53 found no additional survival benefit with the use
of ovarian ablation, progestins or combination hormonal therapy as compared to
Tamoxifen alone (median survival 26 months each, p=0.83, 95% CI 0.82-1.10). These are
shown in table 13 and figure 2.

27
Recommendation:
6. Tamoxifen is the preferred first-line hormonal therapy for patients with metastatic breast
cancer which are estrogen receptor positive. Tamoxifen is given at a dose of 20 mg daily and
is given continuously, even if there is complete response, until disease progression.
( Level I, Category A )
In women who had received prior tamoxifen therapy, progestins, aromatase
inhibitors, androgens or oophorectomy in premenopausal women, can be offered.
Women who responded to a hormonal therapy with either shrinkage of tumor
or long term stabilization are usually offered second line hormonal treatment at the
time of disease progression.
Buzdar et al60 evaluated anastrozole, an aromatase inhibitor versus megestrol
acetate in postmenopausal women with advanced breast cancer which were
predominantly (70%) ER positive and 30% ER unknown. They found an improvement
in median survival of 4 months (26.7 months versus 22.5 months) for patients on
anastrozole compared to progestins. Gershanovich et al 61 also evaluated letrozole,
another aromatase inhibitor versus aminogluthetimide in postmenopausal women
with advanced breast cancer. Results showed that letrozole had better overall survival
(H.R. 0.64; 95% C.I.=0.49-0.85; p = 0.002). Dombernowsky et al.62 also did an RCT
comparing letrozole with megestrol acetate for advanced breast cancer. Results showed
that letrozole had longer time to treatment failure (H.R. 0.77; 95% C.I.=0.61-0.99; p=0.04).
The analysis of 10 other studies (12 comparisons with 3349 patients) 53 also
showed that aromatase inhibitors seemed to perform better than other second-line
hormonal therapies with a 12 percent decrease in the risk of death.
Recommendation:
7. Patients with metastatic breast cancer who responded to tamoxifen initially are offered second
line hormonal therapies at the time of disease progression. ( Level I, Category A )
4. What are the survival benefits of the different chemotherapy regimens in metastatic
breast cancer?
For patients who are not candidates for hormonal treatment, chemotherapy may
be offered.
Systematic review done by the Italian Cochrane Center63 showed no solid
evidence of a survival benefit using chemotherapy regimens in the metastatic setting as
illustrated in table 14 and figure 3.
A Cochrane systematic review done in Australia53 showed evidence that
continued therapy until disease progression was better than limited therapy as
illustrated in table 15 and figure 4. The median survival was 17 months for more cycles

28
versus 13 months for less cycles, p=0.01, 95 % CI 1.01-1.49. However, in keeping with the
primary goal of palliation in the setting of metastatic breast cancer, it is emphasized that
toxicities and complications of chemotherapy be given serious consideration. Palliation
of symptoms should be the primary goal.
Recommendations:
8. For patients with metastatic breast cancer which are estrogen receptor negative, chemotherapy
may increase survival but the size and duration of the benefit is unclear.(Level II, Category A)
9. There is no survival benefit among the different polychemotherapy regimens. Continued
therapy until disease progression is better compared to limited therapy. However, toxicities
and complications of chemotherapy should be given serious consideration bearing in mind that
palliation of symptoms and not tumor response is the main goal of therapy.
( Level I, Category A )
5. Will the addition of chemotherapy to hormonal therapy or the addition of
hormonal therapy to chemotherapy confer a survival benefit for patients with
metastatic breast cancer?
There was level I evidence that chemotherapy did not add any survival benefit to
patients already responding to hormonal therapy.The NHRMC Clinical Trials Centre
and the Cochrane systematic review done in Australia 53 included nine treatment
comparisons from seven trials which assessed the effect of the addition of chemotherapy
in patients who were already receiving endocrine therapy. The combined analysis did
not show a survival benefit for the addition of chemotherapy to endocrine therapy
(median survival 28 months for additional chemotherapy versus 25 months without
additional chemotherapy, p=0.85, 95 % CI 0.85 - 1.32). While the proportions of good
responses were higher in the additional chemotherapy group (62.3 % versus 33.1 %) this
did not result in significant increase in the duration of survival. These are shown in
table 16 and figure 5. The overview by Bergh et al for the Swedish Council of
Technology Assessment in Health Care ( SBU ) 64 arrived at the same conclusion.
There was also level I evidence that hormonal therapy did not add any survival
benefit to patients already responding to chemotherapy. Eleven comparisons from 10
trials included in the same systematic review53 assessed the addition of hormonal
therapy to chemotherapy. Table 17 and Figure 6 show that the combined analysis did
not show a survival benefit for the addition of hormonal therapy to chemotherapy
(median survival 22 months for additional hormone therapy versus 20 months without
additional hormone therapy, p=0.14, 95 % CI 0.97-1.25). Again the higher response rates
seen without the addition of hormone therapy (65.5 % versus 46.3 %) did not result in
longer survival. The systematic review done by the Italian Cochrane Center in Milan 63
and the Swedish overview 64 also arrived at the same conclusion.

29
Recommendation:
10. The addition of chemotherapy to hormonal therapy does not confer a survival benefit for
patients with metastatic breast cancer who are already responding to hormonal therapy.
Likewise, the addition of hormonal therapy to chemotherapy does not confer a survival
benefit for patients with metastatic breast cancer who are already responding to
chemotherapy.( Level I, Category A )
6. Are there other treatments which have shown survival or palliative benefits in
metastatic breast cancer? If so, what are these and what are their survival or
palliative benefits?
Breast cancer patients with metastases confined to the bones had a median
survival of 3-4 years. 65 The relatively indolent course of solitary bone metastases due to
breast cancer allows patients to survive for a considerably long period of time. Thus,
there is a long period of time wherein palliation can be done for symptoms, primarily
pain, due to bone metastases.
Mc Quay et al for the Cochrane Group 66 evaluated the role of radiotherapy in the
palliation of painful bone metastases. Their analyses showed that radiotherapy resulted
in complete pain relief in 25 per cent (395/1580) of patients, and 50 per cent pain relief
in 41 per cent (788/1933) of patients with bone metastases. Numbers needed to treat
(NNT) to achieve complete relief at 1 month (compared with an assumed natural history
of 1/100 patients whose pain resolved without radiotherapy) was 4.2 (95% C.I.= 3.7-4.7).
Onset of relief was within 4 weeks in 52 per cent (394/752) of patients. Median duration
of complete relief was 12 weeks or 3 months. For more generalized disease,
radioisotopes produced similar analgesic results compared to external radiation.
Recommendation:
11. Radiotherapy may be given to symptomatic patients with bone metastases for relief of
symptoms. ( Level I, Category A )
Bisphosphonates may also be given to patients with bone metastases because
they reduce the incidence of skeletal complications and decrease pain medication
requirements; however, no survival benefit has been seen.
Hortobagyi et al67 evaluated the efficacy of pamidronate in 380 patients with
lytic bone metastases and found that patients given 90 mg pamidronate IV for 12 cycles
had longer median time to first skeletal complication (13.1 mos vs. 7 mos ;. p=0.005);
had fewer women developing skeletal complications(43% vs 56% ; p=0.008), reduced the
need for radiotherapy to treat bone pain (19% vs. 33%; p=0.01); and reduced the risk of
pathologic fracture by 50 per cent (O.R.=2.3,95% C.I.= 1.5-3.5) compared with the
placebo group.
Theriault et al68 obtained similar results; patients given pamidronate had longer
median time to first skeletal complication (10.4 mos vs. 6.9 mos; p=0.049); had fewer

30
skeletal complications (2.4 vs. 3.8 ; p=0.008); and had decreased need for radiotherapy to
treat bone pains (25% vs. 34%; p< 0.042).
Paterson et al69 reviewed oral clodronate and found that patients given 1600 mg
daily had fewer hypercalcemic episodes (23% vs 35%; p< 0.01) and fewer incidence of
vertebral fractures (84 vs. 124; p < 0.025).
However, none of the trials showed an impact on overall survival.
Recommendation:
12. For patients with bone metastases, bisphosphonates may be given because they reduce the
incidence of skeletal complications and decrease pain medication requirements; however, no
survival benefit has been seen. ( Level I, Category A )
Summary of Recommendations

A. Locally Advanced Breast Cancer


1. Breast cancer cases which are included in the definition of the Early Breast Cancer
Trialists Collaborative Group (EBCTCG), namely cases wherein cancer is restricted to the
breast and, in the case of node positive patients, the local lymph nodes can be removed
surgically, should be managed according to the PCS evidence based clinical practice
guidelines on early breast cancer (Philipp J Surg Spec 2001; 56(1):7-36).
( Level I, Category A )
2. The term locally advanced breast cancer shall from now on be used for cases that are not
considered early breast cancer and have no evidence of distant metastasis. These will comprise
T4 tumors or stage IIIB cases. ( Level II, Category A )
3. Diagnostic tests for detection of distant metastases in patients with locally advanced breast
cancer should be individualized and symptom-directed; and not done routinely. Physicians
should do exhaustive search for clinical evidence of distant metastases by doing thorough
history and physical examination.( Level II, Category B )
4. There seems to be some evidence that for locally advanced breast cancer, the use of systemic
therapy and radiotherapy may increase survival, but the size and duration of the benefit is
unclear.( Level II, Category A )
5. In some cases, neoadjuvant systemic therapy may reduce primary tumor size to such an
extent that may permit mastectomy or even breast conserving surgery.
( Level II, Category A )
B. Locally Recurrent Breast Cancer
1. Physical examination alone adequately detects locoregional recurrence due to breast
cancer in most cases. ( Level II, Category A )

31

2. Periodic follow-up aimed at early detection of local recurrences of breast cancer may
be recommended, although the prognostic impact of such a policy is probably limited. ( Level
II, Category A )
3. Cytologic or histologic documentation of recurrent disease should be obtained whenever
possible, prior to active treatment. ( Level III, Category A )
4. Core needle biopsy (CNB) is the initial diagnostic procedure in breast cancer patients with a
palpable locoregional recurrence. ( Level III, Category A )
5. Open biopsy, whenever possible, may be done for histologic documentation of recurrent
disease when the initial CNB yields unsatisfactory results.( Level III, Category A )
6. The determination of estrogen receptor ( ER ) status of the local recurrence is encouraged.
However, women with locally recurrent breast cancer with unknown estrogen receptor
status are managed as estrogen receptor positive tumors. ( Level III, Category A )
7. Metastatic work up to evaluate extent of disease is recommended prior to treatment for
recurrent breast cancer. ( Level III, Category A )
8. Salvage mastectomy is the standard treatment for locoregional control of recurrence after
breast conservation treatment. ( Level II, Category A )
9. Radiotherapy is given for locoregional control of locally recurrent breast cancer appearing
after initial treatment with mastectomy. ( Level II, Category A )
10. Surgical resection of local soft tissue recurrence after initial treatment with mastectomy
may be done prior to radiotherapy, for local recurrences measuring 3 centimeters or less,
which could be excised completely and safely, recurring 2 years or more after primary
treatment.( Level II, Category A )
11. Aggressive chest wall resection is not recommended because it carries a high morbidity rate
and there is no proven survival benefit. ( Level II, Category A )
12. For patients with locally recurrent breast cancers which are estrogen receptor positive,
hormonal therapy is the initial systemic treatment given. ( Level I, Category A )
13. Tamoxifen is the preferred first-line hormonal therapy for patients with locally recurrent
breast cancers which are estrogen receptor positive.(Level I, Category A) Tamoxifen is given
at a dose of 20 mg daily and is given continuously even if there is complete response, until
disease progression. ( Level III, Category A )
14. For elderly postmenopausal women with long disease free interval ( 2 years between
primary treatment and local recurrence ) whose recurrence is confined to skin and soft
tissue, locoregional treatment may not be done and tamoxifen alone may be given.
( Level III, Category A )

32
15. For patients with locally recurrent breast cancer which are estrogen receptor negative,
chemotherapy may increase survival but the size and duration of the benefit is unclear. (Level
II, Category A )
C. Metastatic Breast Cancer
1. The primary goal of therapy for patients with metastatic breast cancer is palliation. Palliative
care is the active total care of patients whose disease is no longer responsive to curative
treatment. The goal of palliative care is achievement of the best possible quality of life for
patients and their families. Control of pain and of other symptoms, and alleviation of
psychological, social, and spiritual problems are paramount. ( Level III , Category A )
2. The WHO method of cancer pain relief should be immediately started for all patients with
metastatic breast cancer who complain of pain. ( Level III , Category A )
3. In general, for patients with metastatic breast cancer, systemic chemotherapy may be offered
because it has been shown to confer a modest survival benefit of 6-9 months. ( Level II,
Category A )
4. The determination of estrogen receptor ( ER ) status of the metastatic lesion is encouraged.
However, patients with metastatic breast cancer with unknown estrogen receptor status are
managed as estrogen receptor positive tumors. ( Level III, Category A )
5. For patients with metastatic breast cancer which are estrogen receptor positive,
hormonal therapy is the initial systemic treatment given. ( Level III, Category A )
6. Tamoxifen is the preferred first-line hormonal therapy for patients with metastatic breast
cancer which are estrogen receptor positive.( Level I, Category A ) Tamoxifen is given at a
dose of 20 mg daily and is given continuously, even if there is complete response, until disease
progression. ( Level I, Category A )
7. Patients with metastatic breast cancer who responded to tamoxifen initially are offered second
line hormonal therapies at the time of disease progression. ( Level I, Category A )
8. For patients with metastatic breast cancer which are estrogen receptor negative,
chemotherapy may increase survival but the size and duration of the benefit is unclear.
( Level II, Category A )
9. There is no survival benefit among the different polychemotherapy regimens. Continued
therapy until disease progression is better compared to limited therapy. However, drug
toxicity and complications of chemotherapy should be given serious consideration bearing in
mind that palliation of symptoms and not tumor response is the main goal of therapy.
( Level I, Category A )
10. The addition of chemotherapy to hormonal therapy does not confer a survival benefit for
patients with metastatic breast cancer who are already responding to hormonal therapy.
Likewise, the addition of hormonal therapy to chemotherapy does not confer a survival benefit

33
for patients with metastatic breast cancer who are already responding to chemotherapy.
( Level I, Category A )
11. Radiotherapy may be given to symptomatic patients with bone metastases for relief
of symptoms. ( Level I, Category A )
12. For patients with bone metastases, bisphosphonates may be given because they reduce the
incidence of skeletal complications and decrease pain medication requirements; however, no
survival benefit has been observed. ( Level I, Category A )
ACKNOWLEDGEMENT
This project was supported by a research grant to the Philippine College of
Surgeons from the Philippine Council for Health Research and DevelopmentDepartment of Science and Technology.

34

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a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group.J
Clin Oncol. 1999 Mar;17(3):846-54.
69. Paterson AH, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S. Double-blind
controlled trial of oral clodronate in patients with bone metastases from breast cancer.J
Clin Oncol. 1993 Jan;11(1):59-65.

38
Tables

Table 1. Relative 5-year survival rates for 50,383 patients with breast carcinoma
classified by the AJCC staging. Data taken from the American National Cancer Data
Base ( Commission on Cancer of the American College of Surgeons and the American
Cancer Society ) for the year 1989.
Stage
N
5-year survival (%)
0
5,686
100
I
21,604
98
IIA
10,412
88
IIB
5,673
76
IIIA
1,864
56
IIIB
2,035
49
IV
3,109
16
Table 2 Detection rate of asymptomatic distant metastases from stage III breast cancer
by stage and test.(Ciatto, 1985).
Stage
IIIA
IIIB

Chest X-ray
0.75%
1.20%

Bone X-ray
----2.09%

Bone scan
0.96%
1.33%

Liver echocardiography
____
0.85%

Table 3. Number of examinations to detect one case of asymptomatic distant metastases


from stage III breast cancer according to stage and test. (Ciatto, 1985)
Stage
IIIA
IIIB

Chest X-ray
133
83

Bone X-ray
----48

Bone scan
104
75

Table 4. Summary of data from three randomized controlled trials on locally advanced
breast cancer cases according to treatment and survival rates, 2002.
Trial
Olson9
(ECOG)

Koning10
(Netherlands)
Bartelink11
(EORTC)

TNM Stage
IIA
IIB
IIIA
IIIB
LABC

n
9
21
226
170
118

IIIA
IIIB

111
161

Intervention
MRM + CT/HT
MRM + RT
MRM + OBS
(1)
(2)
(3)
(1)
(2)

RT
RT/CT+HT
CT/RT/CT+HT
RT
RT+CT

Over-all survival
5 yr
8 yr
9 yr
46%
47%
38%
35%
41%
28%
12%
30%
20%
-

10 yr
13%
21%
28%
-

Median
survival
8.3 yrs
8.1 yrs
3.8 yrs

39
others

103

(3) RT+HT
(4) RT+HT+CT

36%
49%

26%
35%

4.3 yrs
5 yrs

MRM mastectomy+axillary dissection; CT chemotherapy; HT hormonotherapy; RT


radiotherapy; OBS observation
Table 5. Disease free-survival by treatment arms of locally advanced breast cancer
patients. (Koning & Hart, 1998)
Treatment
Radiotherapy (RT) alone
Radiotherapy/CMF/Tamoxifen
AV, then RT;AVCMF/Tamoxifen
*p log rank = 0.26

Disease-free survival (%)*


5-year
10-year
11
4
21
15
23
15

Table 6. 5-year survival rates by breast cancer stage. (Pierce, et al, 1992)
Stage
Disease-free survival (%)
Over-all survival (%)
IIIA
55
61
IIIB IBC
33
36
IIIB non-IBC
31
31
IBC- inflammatory breast cancer
Table 7. Survival rates with or without polychemotherapy in node positive early breast
cancer patients.(EBCTCG report on 47 trials),1998.
Age-group
< 50
50 & above

Intervention
5-year survival (%)
with chemotherapy
68.6
without chemotherapy
61.8
with chemotherapy
70.8
without chemotherapy
68.7

10-year survival (%)


53.8
41.4
48.6
46.3

Table 8. Results of two retrospective studies on the prognostic impact of early detection
of breast cancer local recurrences.(Ciatto, 1995)
Asymptomatic
Symptomatic
Recurrences
Recurrences

Ciatto 1984
Disease free interval
5 yr actuarial survival
Median survival

19 months
54 %
75 months

22 months
40 %
60 months

Ciatto 1985
Disease free interval
5 yr actuarial survival

27 months
60 %

30 months
49 %

40
10 yr actuarial survival
Median survival

31 %
45 months

28 %
46 months

Table 9. Performance of fine needle aspiration cytology in the diagnosis of suspected


breast cancer local recurrences. ( Ciatto 1995 )
Recurrence site
Inadequacy
Sensitivity
Specificity
rate ( % )
rate ( % )
rate ( % )
Axilla
1.9
100
100
Internal mammary
25.0
100
100
Chest wall
31.1
94.1
90.5
Supraclavicular
12.7
98.8
100

Table 10. Complications in 93 chest wall resections for recurrent cancer,U.T.M.D.


Anderson Cancer Center, 1989.
WOUND

PULMONARY

OTHER

TOTAL

NO.OF OPERATIONS
W/ COMPLICATIONS

9
4
13

6
4
10

6
6
12

21
14
35

17
12 (12.9%)
29 (30.1%)

MINOR
MAJOR
TOTAL

Table 11. Clinical trials evaluating initial chemotherapy versus initial hormonal therapy
in patients with metastatic breast cancer. NHMRC Clinical Trials Centre and the
Cochrane Collaboration Review Group in Breast Cancer in Australia, 1998.

Exp

Con

Median survival
(months)
N Exp Con Exp/ Con

Priestman T (1978)

CT

ET (various)

92

16

Anon (1986)

AC - > tam tam - > AC

226

19

22

0.86

Combined results 318


(95% confidence interval)

18

18

1.14
(0.02-60.3)

Trial

CT = chemotherapy
ET = endocrine therapy
Exp = experimental arm
Con = control arm
CR = complete response
PR = partial response
AC = adriamycin cyclophosphamide
tam = Tamoxifen

Tumour response
(CR + PR)
p
%
value
Exp
Con
2.29 49
21
0.73

45

22

41
Table 12. Clinical factors that predict response to hormonal treatment in metastatic
breast cancer . (Clinical Evidence, British Medical Publishing Journal Group, 2000 )
Factors predictive of good response to hormonal treatment
Postmenopausal status
Disease limited to soft tissue ( skin, nodes )
ER positive tumor
Long disease free interval since primary treatment for early breast cancer
(> 12- 18 months)
Factors making initial hormonal treatment less appropriate
Symptomatic visceral metastases
ER negative tumor
Short disease free interval (12-18 months)
Relapse on adjuvant tamoxifen (unless ER positive tumor and other features
predictive of good response )
Table 13. Clinical trials evaluating tamoxifen versus other hormonal agents in patients
with metastatic breast cancer. NHMRC Clinical Trials Centre and the Cochrane
Collaboration Review Group in Breast Cancer in Australia, 1998.

Exp

Con

Median Survival
(months)
Exp Con Exp/ Con

Tumour response
CR+PR
p
%
value
Exp
Con

Muss H (1988)

tam

MA 160

136

36

26

1.38

0.12

31

28

van Veelen H
(1986)
Gill P (1993)

tam 40

MPA 900

129

26

20

1.30

35

44

tam

MA

118

19

16

1.19

0.30

26

37

Viladiu P (1985)

CMF + tam

CMF + MPA

65

25

22

1.14

70

68

Ingle J (1986)

tam

Ooph

53

25

24

1.04

0.40

31

35

Perez Carrion RP
(1994)
Smith I (1982)

tam

formestane

409

34

33

1.03

0.70

37

33

tam

AG

117

20

20

1.00

30

30

Castiglione-Gertsch
M (1993)
Gale K (1994)

tam - > AG

MPA - > AG

64

20

22

0.91

0.40

30

50

tam

AG

216

22

26

0.85

35

46

Ingle J (1982)

tam

MA

55

13

17

0.76

0.16

26

14

Muss H (1994)

tam

MPA

182

24

33

0.73

0.09

17

34

Castiglione-Gertsch
M (1993)
Buchanan R (1986)

tam - > MPA

MPA - > tam

60

22

36

0.61

0.40

30

50

tam

Ooph

117

15

25

0.60

0.18

24

21

Combined Results 1721


(95% confidence interval)

26

26

0.95
0.83
(0.82-1.10)

42
tam
= Tamoxifen 20 mg
tam40 = Tamoxifen 40 mg
CMF = cyclophosphamide methotrexate-5 Fu
AG
= aminogluthetimide
MA
= megesterol acetate; MA 160 = megestrol acetate 160 mg
MPA = medoxyprogesterone acetate; MPA 900=medoprogesterone acetate 900 mg
Ooph = oophorectomy

Table 14. Clinical trials evaluating anthracyline based versus non-anthracycline based
chemotherapy regimens in women with metastatic breast cancer. ( Italian Cochrane
Center,1998 )

Mortality rate

79.9 %

80.5 %

43
Table 15. Clinical trials evaluating less versus more cycles of chemotherapy in patients
with metastatic breast cancer. (NHMRC Clinical Trials Centre and the Cochrane
Collaboration Review Group in Breast Cancer in Australia, 1998)

Exp
Ejlertson B
(1993)
Coates A
(1987)
Harris A
(1990)

Con

Median Survival
Tumour response
(months)
(CR + PR)
N Exp Con Exp/
p
%
Con value
Exp
Con
318 23 18
1.28 0.03
52
52

FEC x 24 + tam

FEC x 8 + tam

continuous AC
or CMF
continuous CT

intermittent AC or 305
CMF
intermittent CT
43

11

11

12

Combined Results 666


(95% confidence interval)

17

13
1.23 0.01
(1.01-1.49)

1.22 0.14
0.92

49

32

FEC = 5 Fu-Epirubicin-cyclophosphamide
tam = Tamoxifen
AC = adriamycin cyclophosphamide
CMF = cyclophosphamide- methotrexate 5 Fu
CT = chemotherapy

Table 16. Clinical trials evaluating additional chemotherapy versus no additional


chemotherapy in patients with metastatic breast cancers who were given hormonal
therapy initially. (NHMRC Clinical Trials Centre and the Cochrane Collaboration
Review Group in Breast Cancer in Australia, 1998)

Kiang D (1985) stilboestrol + CF


(ER+)
Ahmann D
ooph + CT
(1982)
Rossof A
ooph + CMF
(1982)
Kiang D (1985) stilboestrol + CF
(ER?)
Bezwoda W
Tam + CMF
(1982)
Anon (1986)
Tam + AC

stilboestrol

Median Survival
Tumour response
(months)
(CR + PR)
N Exp Con Exp/
p
%
Con value Exp
Con
40 72 29
2.48 0.05
86
53

Ooph

76

31

20

1.55 0.90

ooph

40

41

29

1.41

stilboestrol

41

36

tam ->
50
CMF
tam -> AC 226

Abe O (1995)

MPA

Exp

MPA + CAF

Con

48

55

44

33

1.09 0.60

63

23

18

17

1.06

65

63

21

22

0.95

51

22

23

25

0.92

43

24

44
Falkson G
(1979)
Falkson G
(1979)

CF
(ER+)
ooph
CT
CMF
(ER?)
MPA
tam
AC
CAF
cyclo

ooph + CT

ooph

91

26

30

0.87 0.80

75

18

ooph + cyclo

ooph

92

26

32

0.81 0.80

62

18

Combined Results 704


(95% confidence interval)

28

25
1.06 0.85
(0.85-1.32)

= cyclophosphamide 5 Fu
= Estrogen Receptor positive
= oophorectomy
= chemotherapy
= cyclophosphamide-methotrexate-5Fu
= Estrogen Receptor unknown
= medoxyprogesterone acetate
= Tamoxifen
= adriamycin cyclophosphamide
= cyclophosphamide adriamycin 5Fu
= cyclophosphamide

Table 17. Clinical trials evaluating additional hormonal therapy versus no additional
hormonal therapy in patients with metastatic breast cancer given chemotherapy initially.
(NHMRC Clinical Trials Centre and the Cochrane Collaboration Review Group in Breast
Cancer in Australia, 1998)

Author (Year)

Exp

Boccardo F
CMFV/AC + tam
(1995)
Falkson G (1995) CAF + ooph

Median Survival
(months)
Con
N Exp Con Exp/
p
Con value
CMFV/AC 68 34 20
1.70 0.05

Tumour response
(CR + PR)
%
Exp
Con
75
42

CAF

80

42

30

1.40 0.60

84

76

Abe O (1995)

CAF + MPA

CAF

48

23

18

1.28

43

36

Mouridsen H
(1985)
Tominaga T
(1994)
Anon (1986)

CMF + tam

CMF

220

24

19

1.26 0.07

86

51

CAF + MPA

CAF

199

22

19

1.16 0.20

54

37

AC + tam

AC-> tam

226

21

19

1.11

51

45

Viladiu P (1985)

CMF + tam

CMF

67

25

23

1.09

70

46

Perry M (1987)

CAF + tam

CAF

379

21

20

1.05 0.76

64

55

Kiang D (1985)

CF + stilboestrol
(ER-)
CMF + MPA

CF

31

16

16

1.00 0.50

53

29

CMF

64

22

23

0.96

68

46

Viladiu P (1985)

45
Gundersen S
(1992)

CT + MPA 1000

CT

138

13

0.69 0.05

Combined Results 1520


(95% confidence interval)

22

20

1.10 0.14

73

46

(0.97-1.25)

CMFV = cyclophosphamide methotrexate 5Fu vincristine


AC
= adriamycin cyclophosphamide
tam
= Tamoxifen
CAF = cyclophosphamide-adriamycin 5Fu
ooph = oophorectomy
MPA = medoxyprogesterone acetate
CF
= cyclophosphamide 5Fu
CT
= chemotherapy
(ER -) = Estrogen receptor negative
Figures

Figure 1. Ratio of median survival between initial chemotherapy versus initial


hormonal therapy in patients with metastatic breast cancer. NHMRC Clinical Trials
Centre and the Cochrane Collaboration Review Group in Breast Cancer in Australia,
1998.

46
Figure 2. Ratio of median survivals in patients with metastatic breast cancer given
tamoxifen versus other hormonal agents.(NHMRC Clinical Trials Centre and the
Cochrane Collaboration Review Group in Breast Cancer in Australia, 1998)

0.95 (0.82-1.10)
p=0.83

TAM=Tamoxifen

47
Figure 3. Treeplot on the hazard ratios of death of women with metastatic breast cancer
given anthracycline-based chemotherapy versus non-anthracycline based hemotherapy.
Italian Cochrane Center,1998.

Poly = Polychemotherapy
Anthra= anthracycline - based

48
Figure 4. Ratio of median survivals in patients with metastatic breast cancer given
fewer versus more cycles of chemotherapy. NHMRC Clinical Trials Centre and the
Cochrane Collaboration Review Group in Breast Cancer in Australia, 1998.

Figure 5. Ratio of median survival between additional chemotherapy versus no


additional chemotherapy in patients with metastatic breast cancer who were given
hormonal therapy initially.NHMRC Clinical Trials Centre and the Cochrane
Collaboration Review Group in Breast Cancer in Australia, 1998.

49
Figure 6. Ratio of median survival between additional hormonal therapy versus no
additional hormonal therapy in patients with metastatic breast cancer given
chemotherapy initially.NHMRC Clinical Trials Centre and the Cochrane Collaboration
Review Group in Breast Cancer in Australia, 1998.